18-50273590-C-T

Variant names:

• chr18-50273590-C-T
• rs982217875
• NM_015846.4:c.1420G>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_015846.4(MBD1):​c.1420G>A​(p.Ala474Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,460,616 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: MBD1 NM_015846.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.37

Genes affected

MBD1 (HGNC:6916): (methyl-CpG binding domain protein 1) The protein encoded by this gene is a member of a family of nuclear proteins related by the presence of a methyl-CpG binding domain (MBD). These proteins are capable of binding specifically to methylated DNA, and some members can also repress transcription from methylated gene promoters. This protein contains multiple domains: MBD at the N-terminus that functions both in binding to methylated DNA and in protein interactions; several CXXC-type zinc finger domains that mediate binding to non-methylated CpG dinucleotides; transcriptional repression domain (TRD) at the C-terminus that is involved in transcription repression and in protein interactions. Numerous alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.094276756).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MBD1	NM_015846.4	c.1420G>A	p.Ala474Thr	missense_variant	Exon 12 of 17	ENST00000269468.10	NP_056671.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MBD1	ENST00000269468.10	c.1420G>A	p.Ala474Thr	missense_variant	Exon 12 of 17	5	NM_015846.4	ENSP00000269468.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460616 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 726606

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1420G>A (p.A474T) alteration is located in exon 12 (coding exon 11) of the MBD1 gene. This alteration results from a G to A substitution at nucleotide position 1420, causing the alanine (A) at amino acid position 474 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	0.61
DANN	Benign	0.90
DEOGEN2	Benign	0.084	.;T;.;T;.;T;.;.;.;.;.;.;T;T;.;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.051	N
LIST_S2	Uncertain	0.88	D;.;D;.;D;D;D;D;D;D;.;.;D;D;D;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.094	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.14	.;N;.;N;N;N;.;.;N;.;.;.;.;.;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.1	.;N;N;.;N;N;N;N;.;.;.;.;.;N;N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.091	.;T;T;.;T;T;T;T;.;.;.;.;.;T;T;T;T;.
Sift4G	Benign	0.079	T;T;T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.0010, 0.0050, 0.0080, 0.035, 0.0030, 0.0020	.;B;B;B;B;B;B;B;.;.;B;.;.;.;.;B;B;B
Vest4		0.049
MVP		0.55
MPC		0.47
ClinPred		0.036	T
GERP RS		-4.4
Varity_R		0.044
gMVP		0.085

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs982217875; hg19: chr18-47799960;